tbuckley/cabot-search huggingface dataset:
Implementation of universal pan-cancer germline genetic testing in an Arab population: The jordanian exploratory cancer fenetics (Jo-ECAG) study.
Authors: Hikmat Abdel-Razeq, Sarah M. Nielsen, Abdelghani Tbakhi, Hira Bani Hani, Baha' Sharaf, Ramiz Abu Hijlih, Mais Alkyam, Khansa Al-Azzam, Shatha Elemian, Areej Al-Atary, Malek Horani, Zeidan Zeidan, Abdulla Alzibdeh, Emily M. Russell, Brandie Heald, Robert Luke Nussbaum, Edward D. Esplin
Journal: Journal of Clinical Oncology (2023)

10591 Background: Germline genetic testing (GGT) has a significant impact on cancer care. While universal testing has been selectively implemented in the U.S., less is known about adoption of this approach in other ethnic groups. This study reports on GGT results among newly diagnosed cancer patients (pts) in Jordan. Methods: Jo-ECAG was a prospective study of newly diagnosed cancer pts between April 2021 and September 2022 who underwent 84 gene GGT. Patients were classified based on the 2020 National Comprehensive Cancer Network (NCCN) GGT criteria as meeting (in criteria, IC) or not meeting criteria (out of criteria, OOC). Demographics and clinical history were clinician-provided. Pts who were carriers for autosomal recessive conditions were excluded from pathogenic germline variant (PGV) count. Differences in proportions were determined using two-tailed Fisher’s exact test and the significance was set at p≤ 0.05. Results: The cohort consisted of 3,313 Arabic cancer pts, predominantly female (69.8%), with a median age of 54 at testing. Breast was the most commonly diagnosed cancer (50.4%), followed by colorectal (14.9%) and prostate (14.3%). 52% of pts tested were guidelines-based (IC). 460 PGVs were identified in 426 (12.9%) pts. PGVs were most commonly identified in APC (predominantly I1307K variant, 144 pts, 4.4%), BRCA2 (72, 2.2%), BRCA1 (36, 1.1%), CHEK2 (26, 0.8%) and ATM (25, 0.8%). While IC pts were more likely than OOC pts to have a PGV (15.7% vs 9.8%, p&lt;0.0001), 156 (36.6%) pts with PGVs were OOC. 232 (54.5%) pts had PGVs in DNA damage response and repair/homologous recombination repair (DDR/HRR) genes, including 61 (26.3%) OOC pts. 3,602 variants of uncertain significance (VUS) were identified in 2,199 (66.4%) pts with 1,868 of these pts having only VUS results (56.4%), but the frequency in the latter group was not different between IC and OOC pts (p=0.42). Conclusions: Universal GGT of all new cancer pts was successfully implemented and led to actionable findings that would have been missed with guidelines-based testing. With the exception of an overrepresentation of APC I1307K variants, PGV rates were similar to Western ethnic groups. Over half of pts had PGVs in DDR/HRR genes that confer potential eligibility for targeted therapies and/or clinical trials. While VUS rates were high, they were similar between IC and OOC pts. Additional efforts to sequence underrepresented populations and develop variant interpretation methods agnostic to ancestry may help to mitigate these disparities.
Predictive value of co-existing genetic alterations and tumor mutation burden for patients with completely resected non-small cell lung cancer harboring EGFR mutation: Biomarker analysis of phase III IMPACT study.
Authors: Satoshi Ikeda, Masahiro Tsuboi, Kazuko Sakai, Toshihiro Misumi, Hiroaki Akamatsu, Yasuo Iwamoto, Noriaki Sakakura, Atsushi Nakamura, Yasuhisa Ohde, Hidetoshi Hayashi, Kyoichi Okishio, Morihito Okada, Ichiro Yoshino, Jiro Okami, Kazuhisa Takahashi, Norihiko Ikeda, Tetsuya Mitsudomi, Hirohito Tada, Kazuhiko Nakagawa, Kazuto Nishio
Journal: Journal of Clinical Oncology (2023)

8524 Background: Although osimertinib has recently become an option for adjuvant therapy in many countries, biomarkers predicting the efficacy of adjuvant EGFR-TKI and the risk of postoperative recurrence in completely resected NSCLC harboring EGFR mutations have not been fully investigated. Methods: This IMPACT-TR study is an exploratory biomarker study for completely resected, EGFR-mutated NSCLC patients who received gefitinib or cisplatin plus vinorelbine (cis/vin) in a phase III IMPACT study (Trial registration number: UMIN000044738. Funding: AstraZeneca K.K.). Surgically resected lung cancer tissue specimens were analyzed for co-existing somatic mutations and tumor mutation burden (TMB) determined by Oncomine Tumor Mutation Load, and these data were matched with disease free survival (DFS) and overall survival (OS) data. Results: Of the 234 patients in the IMPACT study, 211 patients were enrolled, and 202 patients in the Per Protocol Set were analyzed. The most frequent co-existing somatic mutation was TP53 (58.4%), followed by CSMD3 (11.8%), NOTCH1 (9.9%) and SYNE1 (9.9%). The median TMB was 6.67 mutations/Mb, and only 15.2% had ≥10 mutations/Mb. EGFR mutation subtypes, TP53 co-mutation and TMB were not associated with DFS or OS in either the gefitinib or cis/vin groups. In the gefitinib group, patients with NOTCH1 mutation had significantly shorter OS (hazard ratio [HR] 4.18, 95%CI 1.65-10.61, p=0.003) and tended to have shorter DFS (HR 1.44, 95%CI 0.62-3.37, p=0.399) than those without NOTCH1 mutation. In the cis/vin group, patients with CREBBP mutation had significantly shorter DFS (HR 2.70, 95%CI 1.05-6.97, p=0.040) and tended to have shorter OS (HR 3.05, 95%CI 0.90-10.37, p=0.074) than those without CREBBP mutation. Conclusions: This study suggested that NOTCH1 mutation may be a biomarker to predict poor response to adjuvant gefitinib and CREBBP mutation to predict poor response to cis/vin in patients with completely resected, EGFR-mutated NSCLC. Clinical trial information: UMIN000044738 .
Clinical trial enrollment in a Hispanic-majority NCI-designated cancer center: The Mays Cancer Center experience over 10 years.
Authors: Rodolfo Garza Morales, Anand B. Karnad, Virginia G. Kaklamani, Adolfo Enrique Diaz Duque
Journal: Journal of Clinical Oncology (2023)

e18551 Background: There is a perpetual lack of representation in clinical trial enrollment among minorities. In 2013, the former Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio implemented the Minority Accrual Plan (MAP) to address the challenge of deliberately enrolling minority subjects in clinical trials (CT). The objective of the present study was to describe the racial and ethnic minority representation in CT conducted, at the now Mays Cancer Center (MCC), from years 2012-2021. The MCC is an NCI designated cancer center, that serves a Hispanic (HI) enriched catchment area of 5.1 million people of South Texas. Methods: This is a descriptive analysis of patients enrolled in CT at the MCC from years (y) 2012 to 2021. Patients were enrolled in either interventional treatment (IT), interventional non-treatment (INT), or non-interventional/observational (NI) CT. Variables analyzed included ethnicity, payment class, disease site, and county of origin. Results: We identified a total of 14661 patients with various tumor types who were enrolled in CT at the MCC. A total of 7019 patients (48%) were HI, 6590 patients (45%) were Non-Hispanics (NH), and 1062 (7%) patients did not report ethnicity data. The majority of patients were enrolled on NI (67%), followed by INT (18%) and IT (15%) CT. Overall, the highest enrolled disease sites were genitourinary (40%), breast (11%) and pediatric (7%) cancers. Most patients were self-pay (27%) or had Medicare (27%), whereas 19% of patients had commercial insurance and 7% had CareLink. Enrollment of HI has fluctuated over the years; 4333 HI patients were enrolled from 2012-2016, this decreased to 2686 in the following 2017-2021 period. Overall, 26% of patients were from rural locations, while 74% were from urban locations. The number of rural CT participants was greater in Val Verde (298), Kerr (272), Uvalde (163), and Frio (103) counties. Conclusions: HI continue to be disproportionately enrolled in CT. In 2012, and prior to the implementation of the MAP, 45% of the patients enrolled in clinical trials were HI. In the past 10 years, over 7000 HI patients have participated in CT, even though there have been some fluctuations in accruals rates over the past years, such as in the 2017-2021 period where the COVID-19 pandemic affected enrollment rates. This study validates the notion that better, and perhaps different approaches are needed to improve minority enrollment in CT. Finally, we conclude that the uniqueness of our geographic location did not positively impact HI enrollments. [Table: see text]
Incidence patterns and clinical implications of venous thromboembolisms (VTE) in patients (p) with neuroendocrine tumors (NET).
Authors: Jorge Hernando, Maria Roca, Alejandro Garcia-Alvarez, Sonia Serradell, Amparo Garcia-Burillo, Anna Casteras, Xavier Molero, Xavier Merino-Casabiel, Stefania Landolfi, Laia Blanco, Ignacio Navales, Iratxe Diez, Maria Teresa Salcedo, Marc Simo, Jose Luis Sanchez, Sandra Castro, Simeon Eremiev, Raquel Alvarez, Anna Vazquez, Jaume Capdevila
Journal: Journal of Clinical Oncology (2023)

e24155 Background: Venous Thromboembolisms (VTE) is a common complication in cancer patients (p) and one of the lead causes of cancer-related death. Digestive neoplasms have specific characteristics in VTE incidence and treatment. There is a lack of data regarding VTE impact in p with neuroendocrine tumors (NET). Currently few studies have addressed VTE in NET, with an estimated incidence of 7.5%. Nevertheless, there is no evidence from large datasets to address specific implications of thrombosis in NET p. In the present study, we review incidence and treatment of VTE in NET in a large unicentric cohort. Methods: Consecutive p with gastroenteropancreatic (GEP) and thoracic NET treated in our institution were reviewed to study incidence of VTE including deep vein thrombosis (DVT), pulmonary embolisms (PE) and splanchnic venous thrombosis (SVT). Information regarding clinical characteristics and VTE treatment were collected. Results: 212 p were included in the analysis (38% Female; 42% Pancreatic, 35% Small Intestine, 6.5% lung). 50p presented any kind of thrombotic event (23.5%), and 23 were directly related to TNE (10.8%). Considering 23p with TNE-related VTE (82.3% Male; 82.3% Pancreatic), main origins included: SVT 11p (47.8%) and PE 7p (30.4%). Leading cause of SVT was splenic vein thrombosis. 80.9% of VTE cases received anticoagulant therapy, most of them with low-molecular weight heparin (82.6%) and indefinitely duration (58.8%). All cases that did not started anticoagulant therapy were splenic vein thrombosis due to physician decision. Any complication related to anticoagulant therapy was described in 5p (26.3%). No cases of VTE-related death were found. Conclusions: Patients with NET have a moderate risk of VTE events. Splenic thrombosis is the most common location but need of anticoagulant therapy in those cases remains controversial. Specific studies regarding VTE in NET population are needed.
Efficacy and safety of pembrolizumab every six weeks in relapsed/refractory classical Hodgkin lymphoma or primary mediastinal B-cell lymphoma: The phase 2 KEYNOTE-B68 trial.
Authors: Andrew Bruce McDonald, Estelle Verburgh, Manuel Gotti, Antonio Pinto, Jan Zaucha, Vladimir Ivanov, Vladimir Melnichenko, Heidi Mocikova, Muhit Ozcan, Caterina Patti, Joao Farias, Iara Goncalves, Jiří Mayer, Guray Saydam, Sarah Tomassetti, Kumudu Pathiraja, Katherine Ryland, Samhita Chakraborty, Wojciech Jurczak
Journal: Journal of Clinical Oncology (2023)

7517 Background: Pembrolizumab (pembro) 200 mg Q3W demonstrated robust antitumor activity and manageable safety in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and R/R primary mediastinal B-cell lymphoma (PMBCL), resulting in FDA approval. Recently, the FDA granted accelerated approval of pembro 400 mg Q6W in all approved indications based on data from solid tumor trials in solid tumors. The global Phase 2 trial (NCT04875195) evaluates the efficacy and safety of pembro 400 mg Q6W in R/R cHL and R/R PMBCL. We present, for the first time, data from 66 patients (pts) with approximately 9 months (mo) of follow up. Methods: In this nonrandomized, open-label trial, pts aged ≥18 years with PD-1 inhibitor naïve R/R cHL or PMBCL received 400 mg pembro Q6W for ≤ 18 cycles, until progression, unacceptable toxicity, or withdrawal. Eligible pts with cHL must have relapsed or failed to respond after ≥1 prior lines of therapy (LOT) or relapsed or failed to respond after ≥1 prior multiagent LOT or autologous stem cell transplant (ASCT). Eligible pts with PMBCL must have relapsed or failed to respond after ≥2 prior LOT including rituximab and relapsed or failed to respond to or were ineligible for ASCT. The primary endpoint was ORR per Lugano criteria by investigator (Lugano, INV). Secondary endpoints were DOR (Lugano, INV) and safety. Exploratory endpoints were PFS (Lugano, INV) and OS. Data cut-off date was October 18, 2022. Results: At data cut-off, 66 pts (60 R/R cHL, 6 R/R PMBCL) were enrolled. Median follow-up (range) was 8.9 mo (1 – 15.9) for pts with R/R cHL and 10.6 mo (5.1 – 15.4) with R/R PMBCL. The ORR was 65% (95% CI, 51.6 – 76.9 [33.3% CR; 31.7% PR]) for pts with R/R cHL, and 50% (95% CI, 11.8 – 88.2 [33.3% CR; 16.7% PR]) for R/R PMBCL. Drug-related adverse events (AE) occurred in 24 pts (40%) with R/R cHL and 2 pts (33.3%) with R/R PMBCL. Grade ≥3 drug-related AEs occurred in 3 pts (5%) with R/R cHL and 1 pt (16.7%) with R/R PMBCL. Immune-mediated AEs occurred in 13 pts (21.7%) with R/R cHL and 1 pt (16.7%) with R/R PMBCL. Grade ≥3 immune-mediated AEs occurred in 2 pts (3.3%) with R/R cHL. Antitumor activity is summarized in the Table. Conclusions: With approximately 9 mo of follow up, pembro 400 mg Q6W demonstrates robust antitumor activity in pts with R/R cHL and R/R PMBCL. The ORR observed is similar to pembro 200 mg Q3W in R/R cHL and R/R PMBCL. Pembro 400 mg Q6W had no new safety concerns, confirming Q6W dosing in hematologic indications. Clinical trial information: NCT04875195 . [Table: see text]
Associations between psychosocial and lifestyle factors and biological age acceleration among long-term survivors of childhood cancer: A prospective study from the St. Jude Lifetime Cohort.
Authors: Brennan Streck, Geehong Hyun, Gregory T. Armstrong, Daniel W Belsky, Matthew J. Ehrhardt, Melissa Hudson, Paige Green, Leslie L. Robison, Emily S. Tonorezos, Yutaka Yasui, Zhaoming Wang, Carmen L Wilson, Tara M. Brinkman, Kirsten K. Ness, Jennifer Lyn Guida
Journal: Journal of Clinical Oncology (2023)

10049 Background: Survivors of childhood cancers may be at risk for premature, or accelerated, biological age aging, which is associated with cancer treatment exposures. However, life course theory and a growing body of evidence suggest that psychosocial and lifestyle factors may also contribute. The objective of this study was to explore associations between psychosocial and lifestyle factors and biological age acceleration in the St. Jude Lifetime Cohort. Methods: In this cross-sectional study, we applied physiology-based methods (Klemera-Doubal method and Phenotypic Age) and DNA methylation-based epigenetic clocks (Horvath’s, Hannum’s, Levine’s PhenoAge, GrimAge, and DunedinPACE clocks) to compare biological age acceleration, estimated as the residual from regressing biological age on chronological age, among survivors (n = 4,117) and age- and sex-frequency-matched non-cancer community controls (n = 606). We compared psychosocial and lifestyle factors between survivors and controls using t-tests/Wilcoxan rank sums, and chi-square. Multivariable linear regression was used to assess associations of self-reported smoking, alcohol use, physical activity, overweight/obesity, and depressive symptoms with biological age acceleration in survivors, adjusted for age, race/ethnicity, sex, education, and cancer treatment. Results: Childhood cancer survivors at a mean chronological age of 35.1 years (SD 10.2) were biologically older than controls according to KDM-BA, Phenotypic Age, Hannum’s clock, Levine’s PhenoAge clock, and DunedinPACE, with biological age acceleration ranging from 1.7-4.7 years (p &lt; 0.05.) A greater proportion of survivors reported elevated depressive symptoms (10.3% v. 8.7%), current smoking (17.8% v. 12.3%), &lt; 150 minutes of physical activity (47.3% v. 38.2%), and were overweight/obese (66.0% v. 59.9%) compared to controls (p’s &lt; 0.001). In survivors, &lt; 150 minutes of physical activity (B’s (difference in biological age acceleration [years]) = 1.10-2.68), current (B’s = 1.18-5.96) and former smoking (B’s = 2.53-4.29) were consistently associated with higher biological age acceleration across measures (p’s &lt; 0.05). Risky drinking and higher depressive symptoms were associated with higher biological age acceleration, but only for KDM (B = 1.26, p &lt; 0.021) and DunedinPACE measures (B = 0.15, p &lt; 0.001), respectively. Conclusions: Biological aging in childhood cancer survivors is associated with psychosocial and lifestyle factors. Interventions designed to optimize healthy behaviors and mitigate poor emotional health may have potential to prevent or remediate this phenotype in childhood cancer survivors.
A study of tumor neoantigen burden and HLA-LOH by whole-exome sequencing to characterize immune biomarkers of lung cancer.
Authors: Wei Wang, Wenting Liao, Baoling Zhen, Tianrong Ji, Chen Du, Shaochen Cheng, Yaru Chen, Jie Yang
Journal: Journal of Clinical Oncology (2023)

8527 Background: Lung cancer is a leading cause of cancer-related death worldwide. Precision immunotherapy, such as the use of immune checkpoint inhibitors (ICIs), has been shown to improve the survival of lung cancer patients. Cancer cells with high amount of neoantigens are more likely to be captured by immune cells and thus patients with high Tumor Mutation Burden(TMB) and high Tumor Neoantigen Burden(TNB) are estimated to be prone to ICIs treatment. HLA class Ⅰ is one of the main factors affecting the prognosis of ICI in treatment. Studies have indicated that patients with highly heterozygous HLA-I are more likely to have better responses to ICI treatment. Some specific HLA-Ⅰ genotypes and somatic mutations can affect the prognosis of ICIs treatment. Methods: In this study, we performed whole-exome sequencing (WES) of 200 pairs of tumor and gDNA samples from lung cancer patients. Tumor sample comes from tumor tissue or paraffin-embedded tissue and gDNA is extracted from white blood cells from peripheral blood. We analyze the WES data to obtain the TMB and HLA types of each sample. Then the peptide affinity of MHC-I genes were quantified based on IC50(nM) by netMHCpan software, and the level of neoantigen affinity were classified as strong (IC50≤50nM), weak (50nM &lt; IC50≤500nM), and negative (IC50 &gt; 500nM). TNB is defined as the number of high- affinity neoantigens per megabase of interrogated genomic sequence. Then we conducted linear regression analysis to study the statistical relationship between TMB and TNB. Finally, we analyzed the LOH status at the major region of HLA (HLA-A, HLA-B, and HLA-C) and classified the individuals who have LOH at all three types of HLA as HLA-LOH strong positive, samples with one or two LOH among the three HLA types as weak positive, and samples have no LOH are classified as HLA-LOH negative. Results: Among the 200 samples, the median value of TMB and TNB is 3.25 Muts/Mb and 1.09 Neos/Mb, respectively. 8.5% of the sample have high TMB(TMB≥10). TMB and TNB are also significantly positively correlated (p-value &lt; 0.0001). For HLA typing, 82.0% HLA-A, 96.0% HLA-B, and 92.5% HLA-C are heterozygous. The dominant HLA types are: (A*11:01), (A*02:01), (B*46:01), (B*40:01), (C*01:02), and (C*07:02). As for LOH status among the three HLA types, 14.57% of the individuals are HLA-LOH strong positive, 31.66% are HLA-LOH weak positive, and 53.77% of the samples are HLA-LOH negative. Lastly, the average numbers of detected high-affinity neoantigens are statistically significantly related to the occurrence of HLA-LOH (Analysis of Variance p-value &lt; 0.01). Conclusions: HLA-LOH occurs in nearly half of our lung cancer samples, and it is associated with TMB-High and TNB-High. The analysis of HLA-LOH refines the prediction of neoantigen and gain understanding of drug resistance and immunotherapy.
Cancer risk and characteristics in older female <i>BRCA1/2</i> mutation carriers.
Authors: Bipin Ghimire, Ujjwal Karki, Shiva Shrotriya, Tara Rangarajan, Dana Zakalik
Journal: Journal of Clinical Oncology (2023)

10610 Background: Cancer risk and characteristics in older females with BRCA1/2 mutations are less well studied, and the role of risk-reducing strategies in this population remains unclear. Methods: From a database of 1070 female carriers of BRCA1/2 pathogenic (PV) or likely pathogenic variants (LPV) seen at Nancy and James Grosfeld Cancer Genetics Center in Beaumont Health from January 2006 to December 2021, we identified 283 females who lived to age 65 or older. We analyzed cancer risk and clinical characteristics, focusing on females with cancer diagnosed at age 65 or older. Results: Of the 283 BRCA1/2 carriers, 229 (81%) had a cancer diagnosis, out of which 84 (37%) were diagnosed at age 65 or older. Of all the breast cancer diagnoses (n = 173), 45 (26%) were diagnosed at age 65 or older. Among these 45 patients, median age at diagnosis was 69 years (65-87); majority were BRCA2 carriers (62%), with invasive ductal carcinoma (80%), ER-positive (58%), PR-negative (55%), HER2-negative (97%), high grade (55%) and had stage I or II disease (78%). Fifteen patients (38%) were triple-negative. A minority (32%) received adjuvant chemotherapy, 43% received adjuvant endocrine therapy, and 54% received adjuvant radiation. During a median follow-up of 205 months for all breast cancers (n = 173), there were 52 recurrences, 28 of these (54%) were diagnosed at age 65 or older, of which 13 were contralateral (median time to recurrence: 140 months); 5 were local/regional (median time: 186 months) and 10 were metastatic (median time: 76 months). Ten of the 13 contralateral recurrences (77%) were in BRCA1 carriers. Of the ovarian cancer diagnoses (n = 69), 27 (39%) were diagnosed at age 65 or older. Among these 27 patients, median age at diagnosis was 71 years (65-87); majority were BRCA2 carriers (74%), had serous carcinoma (84%), with stage III or IV disease (96%). Of all ovarian cancers (n = 69), there were 15 recurrences (22%), 9 of them (60%) were diagnosed at age 65 or older. Of the 8 pancreatic cancers, 6 were diagnosed at age 65 or older. Of the 283 BRCA1/2 carriers, 249 still had at least one breast at the time of genetic testing, and 34% elected for risk-reducing mastectomy (RRM). Of the 177 patients with intact ovaries, 71% opted for risk-reducing salpingo-oophorectomy (RRSO). Compared to BRCA carriers with cancer diagnosed under age 65, a smaller proportion of those diagnosed at age 65 or older opted to undergo RRM (26% vs. 40%) or RRSO (67% vs. 78%). Conclusions: Our study reveals that female BRCA1/2 mutation carriers over age 65 continue to retain a significant risk of cancer, including breast, contralateral breast, ovarian, and pancreatic cancer. This finding supports the importance of continued high-risk surveillance and risk-reducing interventions in this growing demographic. Further studies are needed to better define the cancer risks and optimal management of older females with BRCA1/2 mutations.